Chorea

ABSTRACTPurpose of Review: This article reviews the clinical approach to the diagnosis of adult patients presenting with chorea, using Huntington disease (HD) as a point of reference, and presents the clinical elements that help in the diagnostic workup. Principles of management for chorea and some of the associated features of other choreic syndromes are also described.Recent Findings: Mutations in the C9orf72 gene, previously identified in families with a history of frontotemporal dementia, amyotrophic lateral sclerosis, or both, have been recognized as one of the most prevalent causes of HD phenocopies in the white population.Summary: The diagnosis of chorea in adult patients is challenging. A varied number of associated causes require a physician to prioritize the investigations, and a detailed history of chorea and associated findings will help. For chorea presenting as part of a neurodegenerative syndrome, the consideration of a mutation in the C9orf72 gene is a new recommendation after excluding HD. There are no new treatment options for chorea, aside from dopamine blockers and tetrabenazine. There are no disease-modifying treatments for HD or other neurodegenerative choreic syndromes.


INTRODUCTION
Huntington disease (HD) is the most frequent cause of a hereditary neurodegenerative choreic syndrome. HD has a worldwide distribution with some geographic variability in its prevalence. In North America and Europe, the average prevalence is 5 per 100,000 inhabitants. 1 In patients with HD, the initial symptoms occur more frequently between the ages of 30 and 50, although onset can range from childhood/adolescence (juvenile form, also known as the Westphal variant) to individuals older than 70 years of age. HD can present to the clinician with one of three symptom complexes classically described in this condition (motor, cognitive, and neuropsychiatric) or in combination. The motor symptoms include chorea, dystonia, and tics. Chorea has been classically used as the reference manifestation for a clin-ical diagnosis. Parkinsonism usually develops later in the course of the disease. The juvenile form of HD presents as a predominantly hypokinetic movement disorder with parkinsonism but also myoclonus. Of importance, as many as 7% of subjects with a clinical presentation compatible with HD are found to have a negative genetic test for HD and have been coined ''HD phenocopies.'' 2 Spinocerebellar ataxia (SCA) type 17 (SCA17), also referred to as Huntington diseaseYlike (HDL) syndrome type 4 (HDL4), and C9orf72related HD phenocopy in populations of white individuals are considered the most frequent alternative diagnoses. 3,4 The motor and nonmotor elements that help in the diagnostic workup of HD phenocopies in the adult will be discussed later in this article, and a core description of neurodegenerative choreic syndromes is provided in

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Acquired causes of chorea are important to take into consideration since a few can be treated. Certain elements in the clinical presentation of acquired causes of chorea help in the differential diagnosis. Chorea secondary to stroke and drug-induced chorea are among the most prevalent causes of sporadic chorea that a clinician should consider in the appropriate setting. 8 Other sporadic forms of chorea are broadly divided into immune-mediated, infectious, metabolic/endocrine, vascular, and others causes ( Table 8-2). This article covers the approach to adult-onset chorea. As such, conditions with a classic    12 The advent of a genetic diagnosis for HD has shown that most of these cases are, in fact, late-onset HD (Case 8-1). 13 In terms of mode of onset, a relatively acute onset of chorea can be the manifestation of stroke, and also other causes such as nonketotic hyperglycemia, chorea gravidarum, or drug-induced chorea ( Table 8-2). A subacute course over a few days or weeks may be the manifestation of infectious process or autoimmune chorea, including a paraneoplastic syndrome, but does not exclude a metabolic cause. 14 In some cases of drug-induced chorea, a gradual onset may occur, such as in levodopainduced dyskinesia in Parkinson disease (Supplemental Digital Content 8-2, links.lww.com/CONT/A189) or neuroleptic-induced dyskinesia. 15 A more protracted course of months to years is usually associated with a neurodegenerative condition. In terms of the time course of chorea, a slowly

Case 8-1
An 88-year-old woman presented with a 6-to 8-year history of progressive involuntary movements and imbalance, for which she had to use a walker. The involuntary movements were described as ''shaking'' and were increasingly embarrassing to the patient. She had also noticed swallowing air when eating. The patient did not endorse cognitive or mood symptoms, and she lived independently at a retirement home. The patient did not have a family history of chorea. Her examination was remarkable for pronounced generalized chorea involving the limbs, trunk, and face, as well as an inability to walk unaided. A diagnosis of senile chorea was made. The investigations at that time included a head CT, renal and liver function tests, serum glucose, thyroid-stimulating hormone (TSH), as well as anticardiolipin, antiphospholipid, and antinuclear antibodies. All investigations were normal. Genetic testing for Huntington disease (HD) showed a CAG repeat of 39, confirmatory of a diagnosis of late-onset HD. Two years later, the patient died at age 90 with complications from dysphagia and dehydration.
Comment. This case is demonstrative of how to approach a case of senile chorea and how late in life a diagnosis of HD can be made. In a case of senile chorea, a diagnosis of HD has implications for a patient's children, who are at risk of developing HD and may consider predictive genetic testing.
remitting hemichorea is often a case of vascular chorea secondary to a stroke or nonketotic hyperglycemia. The particular case of paroxysmal recurrent chorea suggests a completely different set of diagnoses with consideration of paroxysmal dyskinesias when multiple and short-lived episodes of chorea are reported. Three forms are classically described: paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exertion-induced (or exercise-induced) dyskinesia. Although chorea can present in isolation, the paroxysmal dyskinesias manifest most commonly with both dystonia and chorea in about 60% to 65% of genetically proven cases of paroxysmal kinesigenic dyskinesia (Supplemental Digital Content 8-3, links.lww.com/ CONT/A190) and paroxysmal nonkinesigenic dyskinesia and in about 95% of genetically proven cases of paroxysmal exertion-induced dyskinesia. 16 These conditions have been distinguished on a clinical basis, mainly with respect to the trigger of the episodes, and have been further characterized by the age of onset, duration and frequency of episodes, and response to treatment. In recent years, there has been a significant breakthrough in finding the genetic basis of these conditions (for more information, refer to the following section on investigations and Table 8-3). Psychogenic chorea is rarely reported as a cause of psychogenic movement disorders and typically presents in the form of a paroxysmal movement disorder. 17 Recurrent chorea can also occur in patients with a history of chorea gravidarum or Sydenham chorea who develop chorea when exposed to drugs such as oral contraceptives or phenytoin, although these cases can assume a distinctive pattern of longerlasting episodes separated, at times, by years. 18 The presence of chorea in specific body regions also provides important clues for the differential diagnosis. In forms of neurodegenerative chorea, orofacial chorea frequently associated with dystonia is suggestive of a classic neuroacanthocytosis syndrome (ie, chorea-acanthocytosis (Case 8-2 and Supplemental Digital Content 8-4, links.lww.com/CONT/A191) and, less commonly, McLeod syndrome). 19 Orofacial chorea can also be an early feature of the rare neuroferritinopathy, a late-onset form of neurodegeneration with brain iron accumulation. 20 The dystonic protrusion of the tongue with an associated difficulty maintaining ingested food in the mouth (feeding dystonia) has been classically described in choreaacanthocytosis, but can also be found in other conditions considered in the differential diagnosis of chorea, such as McLeod syndrome, tardive dyskinesia, pantothenate kinaseYassociated neurodegeneration, and Lesch-Nyhan syndrome. 21 In addition, the presence of head drops and truncal/cervical extension is recognized as a distinctive feature of advanced choreaacanthocytosis, but is also described in McLeod syndrome and advanced HD. 22Y24 The presence of tics can be found in HD, but also in the classic neuroacanthocytosis syndromes, particularly in chorea-acanthocytosis. The presence of significant behavioral symptoms in addition to cognitive deterioration strongly suggests a neurodegenerative choreic syndrome, namely HD. In an HD population, apathy is considered the most prevalent behavioral symptom (28.1%), followed by depression, irritability/aggressiveness, and obsessive/compulsive behaviors. 25 Psychosis is less prevalent and can affect as little as 1.2% of the HD population. 25 Behavioral symptoms can precede the onset of motor symptoms and, at the

Case 8-2
A 28-year-old man presented with a 1-year history of difficulty chewing and abnormal gait. In order to eat, the patient swallowed food in big chunks without chewing it. There was no history of seizures, and he was otherwise healthy. There was a known family history of chorea-acanthocytosis in his brother and two paternal cousins. Examination was remarkable for a left gum ulcer, dystonic protrusion of the tongue when ingesting food or speaking, as well as jaw-opening dystonia and recurrent sniffing. He had mild generalized chorea and slight weakness in his hands and feet. Ankle reflexes were absent. Gait was abnormal with hesitations, namely with turns. The investigations identified elevated creatine kinase (422 units/L) and acanthocytes (more than 10%) in the blood. He was started on

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time of a diagnosis based on motor features, deficits in cognitive function can be elicited in formal testing. 26 Suicidal ideation is relatively frequent (8% to 10%) and should be actively looked for, especially in patients with active depression and a previous suicidal attempt. 27 HD phenocopies in which behavioral or cognitive symptoms are part of the clinical presentation include HDL2, chorea-acanthocytosis, and dentatorubral-pallidoluysian atrophy (DRPLA). 28Y30 In McLeod syndrome, behavioral problems are more common and cognitive difficulties are milder. 29 Self-mutilation of the lip and tongue is a clinical manifestation of chorea-acanthocytosis, but is uncommon in McLeod syndrome. 31 Lesch-Nyhan syndrome is an X-linked genetic condition in which patients can have self-mutilating behaviors but the onset occurs in childhood.
Chorea gravidarum, antiphospholipid syndrome, or systemic lupus erythematosus are among nondegenerative causes of chorea that can present with concomitant behavioral symptoms, including personality changes, depression, psychotic symptoms, and cognitive impairment. 18 The occurrence of seizures is a differentiating feature of some HD phenocopies, occurring in about 50% of the cases in chorea-acanthocytosis (30% as presenting feature) and McLeod syndrome, as well as in DRPLA and HDL1, an exceedingly rare entity in which the majority of the cases have seizures. 5,19,30,32 In DRPLA, it is useful to recognize that when the age of onset overlaps the mean age of onset of the adult form of HD, seizures rarely occur, and more common presenting features are chorea, in addition to dystonia, parkinsonism, and psychosis.
When the clinician is considering a genetic choreic syndrome, it is helpful to recognize that certain causes have a higher incidence, in particular, geographic areas or ethnic origins and, thus, should be prioritized whenever applicable. For example, HDL2 has been reported almost exclusively in subjects with a sub-Saharan African ancestry, namely African Americans and black South Africans, and in the rare cases of a presumed non-African origin, an African ancestor could not be ruled out. 33 Neuroferritinopathy has been mostly described in families from the United Kingdom (Cumbria region), with a few cases reported in France and one single case in North America. 34 DRPLA is most frequent in Japan, although it is not exclusive to that country, with rare cases reported in European and North American populations of non-Japanese ancestry. 35 The Haw River syndrome corresponds to a family of African Americans originally from North Carolina, and has been reported as a form of DRPLA. 36

Past Medical History
The presence of acute hemichorea or hemiballismus in a patient with trihexyphenidyl for jaw-opening dystonia with benefit. The patient did not return for follow-up.
Comment. This case shows features suggestive of chorea-acanthocytosis, including the presence of oromandibular dyskinesia with feeding dystonia, tics, as well as signs of peripheral neuropathy. The documented family history of chorea-acanthocytosis and the laboratory findings of elevated creatine kinase and presence of more than 10% of acanthocytes in the blood facilitated the diagnosis.
Continued from page 1194 significant vascular risk factors suggests stroke as a cause, while in a patient with diabetes mellitus, a primary diagnosis of nonketotic hyperglycemia has to be considered in addition. Recurrent miscarriages, migraine, and thrombotic events are a clue for the presence of an antiphospholipid syndrome or systemic lupus erythematosus. Hemodialysis, alcoholism, and malnutrition can point to extrapontine myelinolysis, and the presence of human immunodeficiency virus (HIV) risk factors provide clues to the clinician for HIV-associated causes of chorea (eg, opportunistic infections including toxoplasmosis, progressive multifocal leukoencephalopathy, and HIV encephalitis).
The occurrence of chorea in a pregnant woman should raise the possibility of chorea gravidarum. In the Western world, chorea gravidarum is increasingly rare; currently, its most common causes are antiphospholipid syndrome and systemic lupus erythematosus. 18 In the past, rheumatic fever was the most prevalent cause for chorea gravidarum, but it decreased sharply with the widespread use of penicillin. 18 Family History A clear pattern of inheritance will help the clinician prioritize genetic causes of chorea in the differential diagnosis. However, it is important to recognize that the absence of a family history does not exclude a genetic disorder for many possible reasons, including nonpaternity, de novo mutations (including unstable trinucleotide repeats), premature death of asymptomatic carriers, as well as partial penetrance and phenotypic variability. In fact, genetic causes for chorea are frequently found in sporadic cases (Case 8-1).
In the presence of a family history, an autosomal dominant inheritance pattern is compatible with HD, SCA17, C9orf72-related HD phenocopy, HDL2, as well as DRPLA, neuroferritinopathy, SCA1, SCA2, SCA3, SCA7, and HDL1. 37 In SCA17, most of the cases reported are sporadic or isolated subjects in a family with an ataxic syndrome. Although a family with a SCA17 mutation and multiple members presenting an HD-like phenotype show that phenotypic homogeneity may exist, this is exceedingly rare. 38 For C9orf72-related HD phenocopies, available data suggest a higher prevalence of a positive family history, although with phenotypic heterogeneity within the known spectrum of C9orf72-related clinical presentations. 4 The prevalence of C9orf72-related HD phenocopies should be further assessed as in the initial case series, only three of the 10 cases reported had chorea in their presentation. 4 An autosomal recessive inheritance pattern is compatible with choreaacanthocytosis and aceruloplasminemia. HDL3 also has an autosomal recessive inheritance pattern but has only been described in a Saudi Arabian family. The onset of symptoms is in early childhood, and its presentation resembles the HD Westphal variant. 39 An X-linked recessive inheritance pattern is compatible with McLeod syndrome, although rare female cases have been reported. 40

EXAMINATION
The observation of chorea, other movement disorders, and additional neurologic or systemic signs provides clues for the differential diagnosis. (Supplemental Digital Content 8-5, links.lww.com/CONT/A192; Supplemental Digital Content 8-6, links. lww.com/CONT/A193). Ballismus (derived from the Greek word ballismos, meaning jumping about) is considered a form of chorea characterized by highamplitude movement of a limb in a flinging or flailing motion, including the most proximal segments (Supplemental Digital Content 8-7, links.lww. com/CONT/A194). Athetosis (derived from the Greek word athetos, meaning not fixed) is classically a slow, random, involuntary, writhing movement of the distal region of the limbs and is now recognized to be a manifestation of underlying dystonia, namely in cases of cerebral palsy, and will not be addressed in this article (Supplemental Digital Content 8-8, links.lww. com/CONT/A195).

Chorea Distribution
Particular locations of chorea are suggestive of specific etiologies; aside from the diagnostic value of prominent orolingual and truncal/cervical chorea-dystonia previously described, the presence of hemichorea or hemiballismus suggests a focal structural brain lesion secondary to a vascular event, nonketotic hyperglycemia, and, more rarely, an opportunistic infection in HIV. Nevertheless, instances occur in which hemichorea is a presenting feature of other conditions without a documentable focal brain lesion, examples of which are autoimmune chorea including Sydenham chorea and paraneoplastic syndromes as well as variant Creutzfeldt-Jakob disease. 9,15,41 Conversely, conditions such as nonketotic hyperglycemia can present as generalized chorea 42 (Case 8-3).

Other Movement Disorders
The presence of other movement disorders can help with the diagnosis of a particular chorea syndrome. Dystonic features can be present in HD and in the most prevalent HD phenocopies such as HDL2, SCA17, but also in chorea-acanthocytosis, DRPLA, and neuroferritinopathy (orofacial dystonia), among others. Parkinsonism is a late feature of adult-onset HD at a stage in which chorea is less intense. Nontremulous parkinsonism has been described in neuroferritinopathy, but it is a less common presenting feature (7.5%) compared with chorea (50%) and focal limb dystonia (47.5%). 20 More prominent ataxic features, including eye movement abnormalities (saccadic pursuit, dysmetric saccades, gaze-evoked nystagmus), limb incoordination, and wide-based gait with imbalance should make the clinician suspect an SCA, SCA17 being a more frequent cause. DRPLA can also be considered, and, more rarely, Wilson disease can be considered when ataxia is part of a chorea syndrome. In SCA17, although ataxia is most often present, marked phenotypic heterogeneity occurs, and the presence of a pure choreic syndrome does not exclude this diagnosis. 38 It is worthwhile mentioning that choreic movements are exceptional in other SCAs, such as the example of SCA1, SCA2, SCA3, and SCA7. 37,44 In these cases, ataxia is predominant, and the description of chorea best fits with choreoathetosis. Very rare reports of chorea in other SCAs can be found in the literature: hand choreic movements have been described in SCA14 (PRKCG gene) and in SCA8 (ATXN8/ ATXN8OS gene) gene expansion, although the pathologic role of an expansion in the ATXN8/ATXN8OS gene remains a matter of discussion. 45,46 Apart from eye movement abnormalities consistent with an ataxia syndrome, other changes can be documented when examining a patient with chorea. Difficulty in initiating saccades is classically described in HD.
Other associated neurologic signs may suggest a particular diagnosis: In chorea-acanthocytosis (Case 8-2) and McLeod syndrome, areflexia (Achilles reflex absent in 90% of patients) and limb weakness together with muscle wasting are suggestive of an axonal polyneuropathy and, in some cases, a myopathy has also been documented. 19,47 Patients with SCA1, SCA2, and SCA3 can also have a polyneuropathy. In paraneoplastic syndromes, more commonly there will be other neurologic signs, including peripheral neuropathy, visual disturbances, ataxia, oculomotor disturbances, and behavioral changes with a subacute presentation. 9,48

Systemic Features in Choreic Syndromes
Classic neuroacanthocytosis syndromes are recognized as multisystemic disorders. McLeod syndrome is associated with a cardiomyopathy with atrial fibrillation in 60% of the cases, in addition to hemolytic anemia, hepatomegaly, and splenomegaly. 19 In choreaacanthocytosis, hepatomegaly and splenomegaly are also found. 32 The presence of a photosensitive malar rash and arthritis is suggestive of systemic lupus erythematosus. Signs of thyroid

Case 8-3
A 73-year-old woman presented to the emergency department with an 8-day history of generalized chorea with an acute onset. There was no relevant past medical history, no family history of chorea, and no known use of neuroleptic drugs. Her examination was remarkable for orofacial dyskinesias and generalized chorea. The investigations for vascular and metabolic cases of chorea were remarkable for severe hyperglycemia on admission (more than 500 mg/L). The brain MRI showed bilateral putaminal hyperintensity in T1-weighted imaging (Figure 8-1 43 ). Chorea persisted beyond the normalization of the patient's hyperglycemia. She died 32 days after admission as a result of unresolved sepsis.
Comment. This case shows that nonketotic hyperglycemia may be a cause of acute-onset chorea presenting in a generalized form. The MRI findings highlighted in this case are typical of the syndrome of chorea in the setting of nonketotic hyperglycemia. The MRI findings can be unilateral or bilateral consistent with the side(s) of the body presenting with chorea.  disease suggest the presence of underlying thyroid dysfunction. Anemia, diabetes mellitus, and retinal degeneration are found in aceruloplasminemia. Stigma of chronic liver failure can suggest acquired hepatocerebral degeneration, in which patients can present with orobuccal chorea resembling tardive dyskinesia, in addition to dystonia, parkinsonism, and ataxia, as well as cognitive and behavioral problems. 49 Kayser-Fleischer rings are observed in Wilson disease.

INVESTIGATIONS
An initial panel of investigations should be used to consider treatable causes of chorea and include routine hematology and blood biochemistry tests, in addition to brain MRI and autoantibody testing to identify antiphospholipid syndrome and systemic lupus erythematosus ( Table 8-4). Most of these treatable causes have an acute or subacute onset, which is in striking contrast with a more protracted course of HD and HD phenocopies. As HD is the most prevalent genetic cause of chorea, testing for a pathologic repeat expansion in the HTT gene should be considered, including cases without a known family history for chorea and without an apparent cause after a first round of investigations. In the presence of a symptom complex that points to a specific, albeit rare, cause of chorea, these neurodegenerative conditions can also be considered in a first round of investigations ( Table 8-1).
For HD, a trinucleotide cytosineadenosine-guanine (CAG) equal to or greater than 36 repeats is diagnostic in the presence of characteristic symptoms. In the special case of asymptomatic carriers, a result between 36 and 39 CAG repeats corresponds to incomplete penetrance and uncertainty about phenoconversion in life. As with other neurodegenerative conditions caused by a trinucleotide expansion, a larger number of repeats is associated with an earlier age of onset, and a tendency exists for the number of repeats to increase from generation to generation, manifesting in the form of an anticipation phenomenon for the age of onset. CAG repeats in the intermediate range of 27 and 35 CAG repeats that have been described in rare case reports compatible with symptomatic  HD are associated with significant behavioral abnormalities, with implications for genetic counseling. 50,51 Genetic testing in HD and other neurodegenerative conditions with an adult onset not only impacts the life of the individual being tested, but also his or her family, especially children. For family members at risk, the consideration of predictive testing is usually prompted by wishing to know the carrier status but also for a need to inform life decisions including marriage, parenthood, or a professional career. Genetic counseling is fundamental in order for patients to make a decision about predictive testing in a fully informed and free manner. Risks that are associated with positive predictive testing need to be discussed, including the potential issues of discrimination at work or for insurance purposes, tension in family and personal relations, as well as stress on the patient. Legislation on protection against genetic discrimination exists but varies from country to country and, in the United States, can change from state to state.
A significant proportion of patients presenting as an HD phenocopy currently remain undiagnosed. An alternative diagnosis is found in as low as 2.8% of the cases in tertiary movement disorders centers. 3 In an attempt to prioritize investigations, elements related with differentiating clinical features, ethnic/geographic origin, and family history should be considered as described previously. Available clinical data from case series in tertiary HD centers from Western Europe suggest that SCA17 and C9orf72 gene mutations should be prioritized, particularly in white individuals. 4 HDL2 should be strongly considered in African Americans. Of note, HDL2 may resemble HD more than any other known disease. 52 In a Brazilian cohort, HDL2 and SCA2 were the diagnoses found for HD phenocopies, and there was no diagnosis of SCA17. 53 Among rare genetic entities that have been reported to present as an HD phenocopy and have an available diagnostic test, Friedreich ataxia was reported as an adult-onset choreic syndrome in the sixth decade of life, in association with cerebellar ataxia, and a single case of adult-onset chorea was found to have typical pathology of pantothenate kinaseYassociated neurodegeneration. 3,6 In more recent years, there has been a significant breakthrough in the genetic basis of paroxysmal dyskinesia: the myofibrillogenesis regulator 1 (MR-1) gene and the much less frequent potassium calcium-activated channel subfamily M alpha 1 (KCNMA1) gene were identified in paroxysmal nonkinesigenic dyskinesia, the prolinerich transmembrane protein 2 (PRRT2) gene was identified in paroxysmal kinesigenic dyskinesia, and the glucose 1 transporter (SLC2A1 gene) was identified in paroxysmal exertion-induced (exercise-induced) dyskinesia.
MRI can be helpful in the differential diagnosis of a suspected neurodegenerative choreic syndrome, with attention to patterns of atrophy, presence of signal changes in T1, T2, and fluidattenuated inversion recovery (FLAIR) weighted images, and iron susceptibility imaging. The hallmark feature in clinical MRIs found in adult-onset HD is caudate atrophy (Figure 8-2 have been described. 54 Cerebellar atrophy occurs earlier and more severely in SCAs; in HD, cerebellar atrophy is a late and mild feature. 55 In DRPLA, brainstem and cerebellar atrophy can be found in addition to diffuse T2-weighted hyperintensities in the deep subcortical white matter, and increased iron susceptibility is found in the cerebellum, dentate nuclei, and basal ganglia. 56,57 The presence of a distinctive pattern of iron deposition can suggest and, at times, be diagnostic of neurodegeneration with brain iron accumulation ( Figure 8-3 58 ). In neuroferritinopathy, hypointensities in the dentate nuclei, red nuclei, basal ganglia, thalami, and the rolandic cortex are found even in nonmanifesting carriers. 20 With disease progression, a distinctive bilateral pallidal necrosis with cystic degeneration is observed (Figure 8-3). 20 MRI is also helpful to raise the suspicion or be confirmatory of a diagnosis in sporadic forms of chorea; in patients with chorea due to stroke, a vascular lesion in the subthalamic nucleus is classically described, but chorea can also be associated with strokes in other basal ganglia locations, thalamus, and internal capsule. 59 In the variant Creutzfeldt-Jakob disease, the bilateral hyperintensity in the pulvinar of the thalamus (hockey stick sign), more frequently found in FLAIR sequences, is almost pathognomonic. 60 In nonketotic hyperglycemia, T1-hyperintense lesions in the putamen are observed. 43 In acquired hepatocerebral degeneration, T1 hyperintense lesions are found in the putamen and also in the internal capsule, the mesencephalon, and the cerebellum, in addition to cavitations of the basal ganglia, all thought to be secondary to the deposition of manganese via a portosystemic shunt. 49 The presence of brain calcification, better documented with a head CT, suggests idiopathic basal ganglia calcification once secondary causes are excluded; however, chorea is a rare presentation. 61 Other investigations are to be specifically considered for certain sporadic and genetic causes (refer to Table 8-1 and  Table 8-2), including an antibody panel and search of an occult neoplasm in paraneoplastic chorea.

MANAGEMENT
When chorea is the manifestation of a treatable condition, the main goal of management is treatment of the underlying condition rather than of the chorea itself. This includes removal of the offending drug, normalization of glycemia, immunomodulatory therapy for autoimmune chorea, or removal of an underlying neoplasm.
When these approaches prove to be insufficient or a treatable cause is not found, symptomatic treatment is considered for chorea. Establishing clinical criteria for treatment is the first step in the management of chorea. The clinician should assess the degree of functional incapacity or social embarrassment caused by chorea in a particular individual. However, the lack of insight frequently shown by a patient with chorea relative to the severity of his or her own symptoms can be a limitation for an accurate assessment. In fact, relatives often request treatment. Regardless of the decision, antichoreic medication should be used judiciously as no drug has proven to have a dramatic effect, and adverse effects may have an impact on the functional capacity of patients. Classically, neuroleptics have been used to treat chorea, although the evidence supported by randomized controlled trials is scarce. The only treatment shown to effectively treat chorea, including HD, is the monoamine depleter tetrabenazine. 62 Due to the cost and tolerability profile of this drug, it may be chosen as a secondline drug after the unsuccessful trial of an atypical neuroleptic. Monitoring   of depression, suicidal ideation, akathisia, and parkinsonism are mandatory with tetrabenazine. Pallidal deep brain stimulation (DBS) has been considered as an option for the treatment of pharmacoresistant chorea or ballismus in cases with significant disability, as well as for head drops in chorea-acanthocytosis, with a suggestion of efficacy in HD and chorea-acanthocytosis. 22,63 The treatment of other symptoms in HD phenocopies deserves a special comment. For severe tongue protrusion, it is important to recognize that swallowing and breathing difficulties may be life-threatening. Botulinum toxin injections have been considered in these cases with success, in spite of the risk of temporary dysphagia. 21 Tongue or lip biting can also be treated with botulinum toxin injections or with the use of mouth guards. 21,64 In McLeod syndrome, orthoses may be useful in patients with severe peripheral neuropathy. Patients with head drops such as those found in choreaacanthocytosis (but also in McLeod syndrome and advanced HD) can use head protective gear.
Mood symptoms are generally treated as in general psychiatry, since there are no medications specifically approved for mood disorders in HD and other choreic syndromes. There are no cognitive-enhancing medications with proven efficacy for HD and other choreic syndromes. For the conditions presenting with seizures, general principles for the treatment for epilepsy apply.
In the choreic syndromes that are part of a multisystem disorder, management requires the involvement of different medical specialties. An important example is McLeod syndrome, which requires periodic cardiac assessment due to the presence of cardiomyopathy and the risk of cardiac sudden death.
No disease-modifying therapies are available for HD (although several trials are ongoing) and other neurodegenerative choreic syndromes. In aceruloplasminemia, anecdotal evidence suggests that the use of iron chelators may modify disease biology. 65

CONCLUSION
Chorea is a hyperkinetic movement disorder with a vast list of causes. Aside from sporadic causes, the most prevalent cause of chorea in the adult is HD. The rigorous characterization of the phenomenology and associated neurologic and systemic features will help the clinician prioritize the investigations for the differential diagnosis of choreic syndromes. HD phenocopies represent a challenging diagnostic group; SCA17, C9orf72 in white individuals, and HDL2 in people of sub-Saharan African ancestry, including African Americans, are the most frequent diagnoses, and apart from a few other entities, the vast majority of patients currently remain without a diagnosis. The management of chorea represents a challenge, and the clinician should be able to identify the disability secondary to chorea as the appropriate indication for treatment. When a treatable cause of chorea is present, identification of that cause is mandatory. VIDEO LEGENDS Supplemental Digital Content 8-1 Senile chorea. Video shows a man in his seventies with a clinical diagnosis of senile chorea and who was found to have genetically proven Huntington disease. Mild chorea is seen in the trunk, neck, and orofacial regions, and an exaggerated pout and grimace is seen in the orofacial region.

Supplemental Digital Content 8-2
Levodopa-induced dyskinesia in Parkinson disease. Video shows a 62year-old woman with a 10-year history of Parkinson disease who now has severe, refractory levodopa-induced dyskinesia. After an acute administration of levodopa, she exhibits predominantly choreic dyskinesia that involves the lower limbs, trunk, and, to a lesser extent, the upper limbs.

Supplemental Digital Content 8-3
Paroxysmal kinesigenic dyskinesia. Video shows a man with paroxysmal kinesigenic dyskinesia (PRRT2 gene positive) presenting with chorea and dystonia. Upon standing, a 10-second episode occurs involving the left upper limb with arm adduction, elbow flexion, hand clenching, and choreic movements of the fingers.

Supplemental Digital Content 8-4
Chorea-acanthocytosis. Video shows a 28-year-old man exhibiting jaw-opening dystonia, chorea of the trunk and neck, and dystonic protrusion of the tongue when eating or speaking, but not impaired drinking. Mild bradykinesia and sniffing with nose clearing are also observed.

Supplemental Digital Content 8-5
Chorea in Huntington disease. Video shows florid choreic movements in a man with genetically proven Huntington disease. He exhibits brief, irregular, random, purposeless, involuntary movements flowing from one muscle group to the next, which are superimposed on voluntary motor activity, namely walking.

Supplemental Digital Content 8-6
Chorea of the hands in Huntington disease. Video shows focal chorea localized to the hands of a man with Huntington disease. He exhibits random piano-playing movements of the fingers that are brought about by finger tapping and counting backward.

Supplemental Digital Content 8-8
Athetosis. Video shows a woman with cerebral palsy and athetosis of the right hand. She exhibits characteristic, slow involuntary writhing movements of the distal limb region. Underlying dystonia is evident with prominent lateral deviation and flexion of the wrist and finger extension.